Targeting Viral and Cellular Cysteine Proteases for Treatment of New Variants of SARS-CoV-2
Davide Gentile,
Lucia Chiummiento,
Alessandro Santarsiere,
Maria Funicello,
Paolo Lupattelli,
Antonio Rescifina,
Assunta Venuti,
Anna Piperno,
Maria Teresa Sciortino,
Rosamaria Pennisi
Affiliations
Davide Gentile
Department of Chemistry, Materials and Chemical Engineering “G. Natta”, Politecnico di Milano, Via Mancinelli 7, 20131 Milano, Italy
Lucia Chiummiento
Department of Scienze, University of Basilicata, Viale dell’Ateneo Lucano 10, 85100 Potenza, Italy
Alessandro Santarsiere
Department of Scienze, University of Basilicata, Viale dell’Ateneo Lucano 10, 85100 Potenza, Italy
Maria Funicello
Department of Scienze, University of Basilicata, Viale dell’Ateneo Lucano 10, 85100 Potenza, Italy
Paolo Lupattelli
Department of Chimica, Sapienza University of Roma, p. le Aldo Moro 5, 00185 Roma, Italy
Antonio Rescifina
Department of Drug and Health Sciences, University of Catania, V. le A. Doria, 95125 Catania, Italy
Assunta Venuti
International Agency for Research on Cancer (IARC), World Health Organization, 69366 LYON CEDEX 07, France
Anna Piperno
Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno d’Alcontres 31, 98166 Messina, Italy
Maria Teresa Sciortino
Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno d’Alcontres 31, 98166 Messina, Italy
Rosamaria Pennisi
Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno d’Alcontres 31, 98166 Messina, Italy
The continuous emergence of SARS-CoV-2 variants caused the persistence of the COVID-19 epidemic and challenged the effectiveness of the existing vaccines. The viral proteases are the most attractive targets for developing antiviral drugs. In this scenario, our study explores the use of HIV-1 protease inhibitors against SARS-CoV-2. An in silico screening of a library of HIV-1 proteases identified four anti-HIV compounds able to interact with the 3CLpro of SARS-CoV-2. Thus, in vitro studies were designed to evaluate their potential antiviral effectiveness against SARS-CoV-2. We employed pseudovirus technology to simulate, in a highly safe manner, the adsorption of the alpha (α-SARS-CoV-2) and omicron (ο-SARS-CoV-2) variants of SARS-CoV-2 and study the inhibitory mechanism of the selected compounds for cell–virus interaction. The results reported a mild activity against the viral proteases 3CLpro and PLpro, but efficient inhibitory effects on the internalization of both variants mediated by cathepsin B/L. Our findings provide insights into the feasibility of using drugs exhibiting antiviral effects for other viruses against the viral and host SARS-CoV-2 proteases required for entry.
